Although this invention is being disclosed in connection with cervical cancer, it is applicable to many other areas of medicine. Uterine cervical cancer is the second most common cancer in women worldwide, with nearly 500,000 new cases and over 270,000 deaths annually (IARC, “Globocan 2002 database,” International agency for research in cancer, 2002, incorporated herein by reference). Because invasive disease is preceded by pre-malignant Cervical Intraepithelial Neoplasia (CIN), if detected early and treated adequately, cervical cancer can be universally prevented (D. G. Ferris, J. T. Cox, D. M. O'Connor, V. C. Wright, and J. Foerster, Modern Colposcopy. Textbook and Atlas, pp. 1-699, American Society for Colposcopy and Cervical Pathology, 2004, incorporated herein by reference). Colposcopy is the primary diagnostic method in the United States to detect CIN and cancer following an abnormal cytological screen (Papanicolaou smear or pap smear). The purpose of a colposcopic examination is to identify and rank the severity of lesions, so that biopsies representing the highest-grade abnormality can be taken, if necessary. The biopsies are then microscopically evaluated by a pathologist based on the morphology of the tissue.
For the colposcopic exam, an optical colposcope is typically used, and has been used for such purposes for almost 80 years. A colposcope is a binocular microscope with a built in white light source and objective lens attached to a support mechanism (B. S. Apgar, Brotzman, G. L. and Spitzer, M., Colposcopy: Principles and Practice, W.B. Saunders Company: Philadelphia, 2002, incorporated herein by reference). At low levels of magnification, (comparable to a circular field of view of approximately 50 to 100 mm) the entire vagina and cervix can be visualized and this setting is typically used to obtain a general impression of the surface structure and architecture. Medium magnifications (comparable to a circular field of view of approximately 15-30 mm) and high magnifications (comparable to a circular field of view of approximately 5-15 mm) are utilized for detailed analysis of the vagina and the cervix. These higher magnifications are often necessary to detect and identify certain vascular patterns indicative of the presence of more advanced pre-cancerous or cancerous lesions. During the colposcopic exam, acetic acid and iodine solutions are usually applied to the surface of the cervix to improve the visualization of abnormal areas. In addition, different colored filters are often used to accentuate blood vessel patterns that cannot be easily seen by using regular white light.
Although the standard colposcopic exam and regular screening have led to dramatic decreases in the overall incidence of cervical cancer, new technologies can further enhance the sensitivity and specificity of currently accepted colposcopic practices. Digital imaging is one such technology that can revolutionize medical imaging and enables sophisticated computer programs to assist the physician with CAD (Computer-Aided-Detection or Computer-Aided-Diagnosis). The combination of digital imaging and CAD could have a direct impact on improving women's health, and decrease the associated cost, by automatically identifying CIN in real-time with high sensitivity and specificity. This would mean fewer false-positive biopsies, or ultimately, elimination of biopsies. A CAD system operating as an adjunct to colposcopy could minimize the high variability among colposcopists and enable consistent, higher standards for accuracy. A product realization where a CAD system is incorporated into a low-cost device, creating in effect a machine expert colposcopist, would have the potential of increasing the availability and cost-effectiveness of screening in developing countries.
Digital imaging provides a means for implementing a computerized clinical data management system. This data management system could provide management, display, and annotations of the acquired digital data, as well as automation of the workflow associated with colposcopy. The system could simplify the administration of patient data and history, allow the use of electronic patient data records, and interface and integrate with standard systems for handling, storing, printing and transmitting information in medical imaging, such as DICOM (Digital Imaging and Communication in Medicine). DICOM is a standard for handling, storing, printing, and transmitting information in medical imaging. It includes a file format definition and a network communications protocol. The communication protocol is an application protocol that uses TCP/IP (the standard internet protocol) to communicate between systems. DICOM files can be exchanged between two entities that are capable of receiving image and patient data in DICOM format. Digital imaging alone is also a pre-requisite for telemedicine applications, further increasing the availability of screening and detection in rural areas and developing countries.
In order to reliably assess colposcopic features, the imagery upon which a CAD system operates must be of high visual quality. One factor contributing to poor cervical imagery is specular reflection (glint), which is perfect, mirror-like reflection of light from a surface, in which light from a single incoming direction (i.e., a ray) is reflected into a single outgoing direction. Glint is undesirable because it effectively eliminates color information in an image, and also results in the introduction of artifacts (misrepresentations of tissue structures) in the image. Glint eliminates color information because its mirror-like reflection shows the color of the light source, and not of the underlying tissue, much as a mirror shows the color of a reflected light, and not the color of the mirror itself. Because this color information may be important in detecting cancer precursors, reducing the amount of glint in an image is helpful in producing high-quality images for diagnostic purposes. However, it is not always desirable to eliminate all the glint from an image because an image of a tissue or organ that contains glint may look more natural and three-dimensional. In addition, colposcopists analyze the glint patterns on the cervix to assess the surface contour of lesions, an important feature used to evaluate lesion severity.
The prior art describes a number of ways to reduce the influence of or eliminate glint. Physicians using optical colposcopes can change their field-of-view and/or the lightning conditions to either move the glint to different parts of the cervix and maintain the region of interest glint-free, or to a large extent eliminate the glint completely. Another method involves using multiple light sources directed at different angles towards an object (see for example K. T. Schomacker, T. M. Meese, C. Jiang, C. C. Abele, K. Dickson, S. T. Sum, and R. F. Flewelling, Novel optical detection system for in vivo identification and localization of cervical intra-epithelial neoplasia, J. Biomed Optics 11(3), 034009-1-12, 2006, and J. E. Kendrick, W. K. Huh, and R. D. Alvarez, LUMA™ Cervical Imaging System, Expert Rev. Med. Devices 4(2), 121-129, 2007, incorporated herein by reference). By illuminating the cervix at different angles and acquiring several images, the position of the glint on the surface of the cervix is different between the different images, and the images can be combined to create a glint-free combined image.
The use of polarization filters, each of which functions in the same way as a pair of polarized sunglasses, is another glint reducing or eliminating technique well known in the art (see for example, E. Hecht., Optics, Addison-Wesley, 1st edition 1972, 2nd edition 1987, 3rd edition 1997, 4th edition 2001). The polarization filter method utilizes one polarization filter placed at the light source and another filter rotated to approximately 90° positioned in front of the detector. By applying this cross polarization scheme, the reflections from the surface of the object under study are substantially minimized, if not completely eliminated, and the end result is an essentially glint-free object or image. Cross-polarization is employed, for example, in commercially available colposcopes (Welch Allyn Video Colposcope, User's manual, 2007, incorporated herein by reference), and research colposcope systems (such as described in S. Nakappan, S-Y. Park, D. Serachitopol, R. Price, M. Cardeno, S. Au, N. Mackinnin, C. MacAulay, M. Follen, and B. M. Pikkula, Methodology of real time quality control for the multispectral digital colposcope, Gynecologic Oncology 107, S21-S222, 2008, incorporated herein by reference). In these systems, the polarization filters are typically actuated by computer controlled rotating filter wheels or manually operated rotating filter holders, either on the light source side or detection side, or both. Being able to remove or rotate the polarization filters, allows for the acquisition of both cross-polarized imagery without glint and regular imagery with glint. A drawback of using manually operated or computer controlled mechanical assemblies to switch or rotate the polarization filters is the inevitable wear and tear and ultimate failure of these units over time. In addition, mechanical switch or rotational devices will introduce a delay between the image viewing or capture of cross polarized and regular imagery. During this delay, significant movement of the colposcope and/or the patient can occur. This movement can make it extremely difficult to register (align) images and track diagnostically important features, such as blood vessels of varying sizes. This is especially true for a fully automated CAD system that does not rely on human direction or intervention.
Another factor contributing to poor cervical imagery, with respect to imaging systems incorporating polarizing components, is that polarization inherently results in a loss of light. Because brightness (or intensity) is an integral part of the achievable contrast (i.e. the difference in visual properties that make an object distinguishable from other objects and the background) in the captured images, and because the contrast of an image is important in detecting cancer precursors such as vascular patterns, bright light sources are helpful in preserving the clarity of an image.
However, these bright light sources must not exceed acceptable thresholds for patient exposure to ultraviolet (UV) and infrared (IR) radiation (as described by the American Conference on Governmental Industrial Hygienists (ACGIH) in, Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs), Signature Publications, 2008, incorporated herein by reference). Exposure to UV radiation has the potential of acute adverse health effects such as erythema and photokeratitis, and can cause DNA damage in the cells. Presently, the exposure to UV radiation is minimized, if not completely eliminated, by employing a UV blocking filter in the light source beam path prior to the light being available to human viewing and exposure (such as described in Welch Allyn Video Colposcope, User's manual, 2007, incorporated herein by reference) and S. Nakappan, S-Y. Park, D. Serachitopol, R. Price, M. Cardeno, S. Au, N. Mackinnin, C. MacAulay, M. Follen, and B. M. Pikkula, Methodology of real time quality control for the multispectral digital colposcope, Gynecologic Oncology 107, S21-S222, 2008, incorporated herein by reference). Many bright light sources also contain a large amount of IR which is essentially excess heat. Similar to UV radiation, the exposure to IR radiation is minimized or eliminated by the utilization of an IR blocking filter. Although the heat exposure of the user or patient is minimized or eliminated by an IR blocking filter, the heat generated by the IR radiation puts stress on the optical and mechanical components of the light source assembly and may significantly decrease the lifetime of the components, as well as of the light source itself.
Further, some bright light sources require a long start-up time before the output intensity is stable. This means there is a wait time before the device can be utilized in a clinical examination, possibly decreasing the cost-effectiveness of such a device.
A third factor contributing to poor cervical imagery is non-uniform lighting, which can lead to non-uniformity of the brightness (or intensity) in the resulting image. Non-uniformity of brightness impairs the potential accuracy of any diagnosis based on the resulting image.
The following patents may be considered relevant to the field of the present invention:
U.S. Pat. No. 4,979,498 to Oneda et al., incorporated herein by reference, discloses a video cervicoscope system for the examination of the cervix comprising: a rigid, elongated tubular member having a light guide; imaging means at the distal end of said tubular member, a disposable, light-transmitting, sleeve disposed about the distal end of said tubular member; and transmitting means to transmit an image viewed by said imaging means proximally to a control box wherein said image is received and stored.
U.S. Pat. No. 5,836,872 to Kenet et al., incorporated herein by reference, discloses a method for monitoring a region of a body surface which includes recording at a first time a first multispectral digital image of the surface including the region, recording at a subsequent time a subsequent multispectral digital image of the surface including the region, and comparing the first and the subsequent images. Also, such a method in which the first and subsequent images are high magnification images, and further including recording low magnification images that include the high magnification images. Also disclosed is a method for forming a diagnostically useful classification of pigmented skin lesions, using such a method to construct a database containing quantitatively extracted selected features from images recorded from a plurality of skin lesions, and correlating the features from each such lesion in the database with the medical history of the skin lesion from which the image was recorded. Further, a method for diagnosis of a premelanomatous or early melanomatous condition includes using the method for characterizing a surface region including the lesion and comparing the features of the lesion so obtained with the features in a database obtained from a number of skin lesions including lesions known to be premelanomatous or early melanomatous, or classifying the features of the lesion according to the diagnostically useful classification of pigmented skin lesions.
U.S. Pat. No. 5,929,443 to Alfano et al., incorporated herein by reference, discloses a method and apparatus for the imaging of objects based on the polarization and depolarization of light. In one embodiment, a surface of a turbid medium is imaged by illuminating the surface of the turbid medium with light, whereby light is backscattered from the illuminated surface of the turbid medium, detecting a pair of complementary polarization components of the backscattered light, and forming an image of the illuminated surface using the pair of complementary polarization components. The illuminating light is preferably polarized (e.g., linearly polarized, circularly polarized, elliptically polarized), where, for example, the illuminating light is linearly polarized, the pair of complementary polarization components are preferably the parallel and perpendicular components to the polarized illuminating light, and the image is formed by subtracting the perpendicular component from the parallel component, by taking a ratio of the parallel and perpendicular components or by using some combination of a ratio and difference of the parallel and perpendicular components.
U.S. Pat. No. 5,989,184 to Blair, incorporated herein by reference, discloses an apparatus for digital colposcopy and videography which comprises a digital imaging camera that is operably coupled to the optical path of the digital colposcope by means of a beam splitter so that a digital image of the cervico-vaginal tissue can be captured. The digital imaging camera and digital colposcope are mounted to one end of an articulating arm of the apparatus. Digital processing means is operably connected to the digital imaging camera to create a digital image. The digital processing means is housed in a stand of the assembly.
U.S. Pat. No. 6,277,067 to Blair, incorporated herein by reference, discloses a method and portable apparatus for the visual examination and grading of cervical epithelium by means of a hand-held colposcopy assembly capable of producing a digital image of the cervix. The apparatus enables real-time imaging and archiving of images of the entire cervix for the purpose of detecting cancerous and pre-cancerous tissue, and by virtue of computerized image processing, suggests an objective diagnosis of the cervical epithelium by means of a low cost, portable, hand-held digital colposcope.
U.S. Pat. No. 6,587,711 to Alfano et al., incorporated herein by reference, discloses an apparatus for examining an object, such as skin, mucosa and cervical tissues, for the purpose of detecting cancer and precancerous conditions. In one embodiment, the apparatus includes a gun-shaped housing having a handle portion and a barrel portion. The front end of the barrel portion is open, and a glass cover is mounted therein. Red, green, blue, and white LED's are disposed within the handle portion of the housing, and are electrically connected to a battery and are also disposed within the handle portion of the housing. A manually-operable switch for controlling actuation of each of the four LED's is accessible on the handle portion of the housing. An optical fiber is disposed inside the housing and is used to transmit light from the four LED's through a first polarizer disposed in the barrel portion of the housing and then through the glass cover to illuminate a desired object. Reflected light from the object entering the housing through the glass cover is passed through a second polarizer, which is adjustably mounted in the barrel portion of the housing and which is preferably oriented to pass depolarized light emitted from an illuminated object, and is then imaged by optics onto a black and white CCD (charged coupled device) detector (camera). The optics may include a lens that is disposed within the barrel portion and is adjustably spaced relative to the CCD detector. The detector is coupled to a wireless transmitter mounted in the housing, the transmitter transmitting the output from the detector to a remotely located wireless receiver. The wireless receiver is coupled to a computer, which then processes the output from the detector. The processed output is then displayed on a display. The display may be remotely situated for remote expert diagnosis.
U.S. Pat. No. 6,766,184 to Utzinger et al., incorporated herein by reference, discloses methods and apparatus for generating multispectral images of tissue. The multispectral images may be used as a diagnostic tool for conditions such as cervical cancer detection and diagnosis. Primary radiation is produced with an illumination source. The primary radiation is filtered to select a first wavelength and a first polarization. Tissue is illuminated with the filtered primary radiation to generate secondary radiation, which is filtered to select a second wavelength and a second polarization. The filtered secondary radiation is collected with a detector, and a plurality of multispectral images of the tissue is generated according to different combinations of first and second wavelengths and first and second polarizations with an analysis unit in operable relation with the detector. Apparatus utilizing the invention include endoscopes and colposcopes.
U.S. Patent Application Publication No. 2006/0141633 to Balas, incorporated herein by reference, discloses a method and an apparatus for the in vivo, non-invasive, early detection of alterations and mapping of the grade of these alterations, caused by the biochemical and/or the functional characteristics of epithelial tissues during the development of tissue atypias, dysplasias, neoplasias and cancers. The method is based on the simultaneous measurement of the spatial, temporal and spectral alterations in the characteristics of the light that is re-emitted from the tissue under examination, as a result of a combined tissue excitation with light and special chemical agents. The topical or systematic administration of these agents results in an evanescent contrast enhancement between normal and abnormal areas of tissue. The apparatus enables the capturing of temporally successive imaging in one or more spectral bands simultaneously. Based on the measured data, the characteristic curves that express the agent-tissue interaction kinetics, as well as numerical parameters derived from these data, are determined in any spatial point of the examined area. Mapping and characterization of the lesion are based on these parameters.
U.S. Patent Publication No. 2006/0184043 to Tromberg et al., incorporated herein by reference, discloses an improvement in a method for quantitative modulated imaging to perform depth sectioned reflectance or transmission imaging in a turbid medium, such as human or animal tissue. The method is directed to the steps of encoding a periodic pattern of illumination, preferably with a fluorescent excitation wavelength when exposing a turbid medium to the periodic pattern, to provide depth-resolved discrimination of structures within the turbid medium; and reconstructing a non-contact three dimensional image of the structure within a turbid medium. As a result, wide field imaging, separation of the average background optical properties from the heterogeneity components for a single image, separation of superficial features from deep features based on selection of spatial frequency of illumination, or qualitative and quantitative structure, function and composition information, is extracted from spatially encoded data.
U.S. Patent Application No. 2006/0215406 to Thrailkill, incorporated herein by reference, discloses a medical diagnostic instrument, which could be a colposcope for examining cervical tissue, and includes a light source comprising an annular array of high intensity light emitting diodes (LEDs). The LED array includes a central access opening which provides viewing access for the colposcope optical components to the illumination site. The array includes a plurality of sets of LEDs, with each set including a red, blue and green emitting LED. The intensities of the red, blue and green LEDs, respectively, are controllable with a controller to continuously vary or tune the spectral characteristics of the illumination from the light source. Selected color mixes can be stored in a memory for later retrieval.
U.S. Patent Publication No. 2007/0213590 to Squiccinarini, incorporated herein by reference, discloses a portable multi-functional endoscopic device and method for use in the examination of tissue to permit diagnostic, therapeutic or anatomical assessment data to be transmitted, recorded, or analyzed. The device includes a base unit sized and configured to be held in a human hand to permit functional and directional control of the device, an interchangeable head assembly sized and configured to be inserted into an orifice being removably connectable to the base unit, and an inflatable tissue stabilizer disposed external to a distal end of the device. In preferred aspects, the endoscopic device has an image sensor, light source, lens, air pump, and working tools.
U.S. Patent Application No. 2008/0049997 to Chin, incorporated herein by reference, discloses an image enhancement system that includes a data source which provides image data of an object, enhancement data storage including image enhancement information, an image enhancement unit configured to enhance the image data based on the image enhancement information, and a color display configured to display a monochrome image representing the enhanced image data on a screen thereof. The enhanced image data may include a gray level scale of at least 32 bits per pixel.
U.S. Patent Application Publication No. 2005/004365 to Zelenchuk, incorporated herein by reference, discloses a system and method for the in situ discrimination of healthy and diseased tissue. A fiberoptic probe is employed to direct ultraviolet illumination onto a tissue specimen and to collect the fluorescent response radiation. The response radiation is observed at three selected wavelengths, one of which corresponds to an isosbestic point. In one example, the isosbestic point occurs at about 431 nm. The intensities of the observed signals are normalized using the 431 nm intensity. A score is determined using the ratios in a discriminant analysis. The tissue under examination is resected or not, based on the diagnosis of disease or health, according to the outcome of the discriminant analysis.